Project Summary A striking example of the potential for adult lung growth occurs after pneumonectomy. In most mammals, including humans, removal of one lung results in the growth of the remaining lung. Preliminary data in mice and humans indicates that the lung heals in response to local mechanical forces. The mechanism of lung remodeling is ?epithelial-mesenchymal transition? (EMT). Exposed to mechanical forces, the pleural mesothelium of the lung undergoes the dramatic phenotypic and functional transition characteristic of EMT. The central hypothesis of this application is that is that EMT is inducible in pleural mesothelium by mechanical forces; that is, optimized mechanical forces trigger EMT with subsequent transitional cell migration into the lung. The centripetal migration of these transitional mesenchymal cells leads to alveolar remodeling and lung growth. To test this hypothesis, a pectin-based bioadhesive will be used to isolate surface-view or en face pleural mesothelium. The stretch signals will be defined both in vivo and in vitro. The isolated en face pleural mesothelium will be used to define the pleural (morphologic, phenotypic, transcriptional) response to surgical stretch manipulations in vivo. The isolated ?normal? pleural mesothelium will be stretched in a mechanical bioreactor to define the pleural response to stretch manipulations in vitro. These objectives correspond to three specific aims. Specific Aim #1: Isolate visceral pleura mesothelium using pectin-based bioadhesives. Specific Aim #2: Define the pleural mesothelium EMT response to surgical manipulations in vivo. Specific Aim #3: Define the EMT response of pleural mesothelium to patterns of stretch (variations in duration, frequency and amplitude) in vitro. The long-term goal of our project is a fundamental understanding of the role of mechanical forces in the remodeling and repair of the lung. These basic mechanisms of lung repair will not only be useful in the practical management of lung disease, but provide mechanistic insights into the structural perturbations observed in diseases as diverse as pulmonary fibrosis and emphysema.